Ewing sarcoma

Ewing sarcoma is a rare cancer that can form in bone and soft tissue. It belongs to a group of tumours known as the Ewing Sarcoma Family of Tumours.

The Ewing family of tumours includes:

• Ewing sarcoma - a form of primary bone cancer
• Extraosseous Ewing sarcoma - a tumour that starts in soft-tissue rather than the bone
• Askin tumour - Ewing sarcoma that starts in the chest wall
• Primitive Neuroectodermal Tumour - Ewing sarcoma where the cells look like nerve cells when studied under the microscope

The majority of Ewing sarcomas (around 85%) start in the bones, but they can also start in the soft tissues as well.

Ewing sarcomas is the second most commonly diagnosed primary bone cancer in young people, after osteosarcoma.

Ewing sarcoma can start anywhere in body, but more often it is found in the pelvis, the chest or in the bones of the legs.

Figure 1. Where does Ewing Sarcoma occur most often?

Image: Hannah Thompson

Ewing sarcoma and osteosarcoma occur in slightly different places in the skeleton. Osteosarcoma usually starts in the ends of the bone, and less often in the middle (shaft) of the bone.

Ewing sarcoma arises from any point in the bone with almost equal frequency. Ewing sarcoma is more commonly found in flat bones (e.g. the ribs or the pelvis) than osteosarcoma.

Figure 2. What are the different parts of a long bone?

Image: Hannah Thompson

Ewing sarcoma can spread to other parts of the body

Ewing sarcoma can quickly spread to other parts of the body and can sometimes come back after treatment (recur), and so patients require treatment to the whole body (systemic) as well as the site of the primary tumour.

Tumour cells can break away from the primary tumour and enter the blood supply or lymphatic system. These tumour cells can travel to other parts of the body where they can settle and form new tumours called secondary tumours or metastases. The tumour cells can also spread through the bone as the tumour grows.

The most common sites for secondary tumours are:

• the lungs
• other bones
• the bone marrow

Very rarely the cancer can spread to the lymph nodes, liver or brain.

Treatment is usually a combination of chemotherapy, surgery and radiotherapy. Wherever in the body Ewing sarcoma starts, the treatment is the same.

• There are fewer than 100 cases of Ewing sarcoma diagnosed in the UK and Ireland each year.
• In the general population in Europe each year, there are slightly less than two cases of Ewing sarcoma diagnosed per million people (1.90 / 1,000,000). This is known as the incidence rate.
• In the USA, the incidence rate is higher than the European rate at 2.9 cases per million people.
• Ewing sarcoma can occur at any age but it is very rare in people over the age of 30.
• The peak of incidence (between 10 and 20 years of age) of Ewing sarcoma patients corresponds with times at which a person's bones are growing fastest. The average age of patients with Ewing sarcoma is 15 years.
• Overall, Ewing sarcoma occurs more often in males compared to females. However, in the 0-14 age group, males and females appear to be equally affected.
• Ewing sarcoma accounts for around 1.5% of all childhood cancers.
• Survival rates for Ewing sarcoma have not significantly improved over the past 30 years.

There has been a lot of research into possible causes of Ewing sarcoma but the exact cause remains unknown.

Like osteosarcoma, the development of Ewing sarcoma may be related in some way to periods of rapid bone growth. This may explain why most cases of Ewing sarcoma are seen in adolescents.

Risk factors for Ewing sarcoma

A 'risk factor' is something that increases your chance of getting a disease.

There are no known inherited risk factors (hereditary factors) that cause Ewing sarcoma.

There is no confirmed link between any environmental factors and Ewing sarcoma.

Some small-scale research has found that Ewing sarcoma is seen more often in people who live in the countryside than in people who live in cities.

Known risk factors

• Gender: Ewing sarcoma is more common in males than females (1.6 boys are diagnosed to every 1 girl)
• Age: Most cases of Ewing sarcoma are diagnosed between the ages of 10 and 20 years old.
• Race: Ewing sarcoma seems to be less common in people of African-Caribbean or Chinese origin, compared with Caucasian people.

Can Ewing sarcoma be prevented?

As the causes of Ewing sarcoma are not fully understood, we don't know how to prevent it from happening.

Presentation: doctors talk about 'presentation' when they mean 'symptoms' and 'clinical signs'.

Symptoms: these are the feelings and signs that a patient or a parent/ carer sees or feels, which signal that the patient is ill.

Clinical signs: these are what the doctors may see during a physical examination, giving doctors clues about what is wrong with the patient.

The most commonly reported symptoms of Ewing sarcoma are:

• Localised pain at a specific place in or near a bone. The pain may come and go over time and can vary in its intensity.
• Swelling around a bone or joint can be seen if a tumour is near the skin. Swelling is not always visible because if a tumour is deep inside the body, such as in the pelvis, it may be hidden from view.

Less common symptoms, rare, and very rare symptoms include:

• fever (known as pyrexia)
• tiredness or feeling weary (referred to as lethargy or fatigue)
• pain accompanied by tingling and numbness (pins and needles)
• weight loss and loss of appetite
• breathlessness.

Symptoms vary from patient to patient and can range in their severity and there is no definitive list. Symptoms may be mild at first, coming on over a period of a couple of weeks, but they may appear suddenly. Some patients report their symptoms disappearing for relatively long periods before suddenly returning.

Symptoms may be present for weeks or months, sometimes even longer before patients are diagnosed. This can be because the symptoms of Ewing sarcoma are quite general and could indicate a number of conditions. Some examples of these in older children, adolescents and young adults include:

• Tendonitis - an inflammation of the tendons.
• Osgood-Schlatter disease - inflammation of the growth plate where the knee cap tendon inserts.
• Trauma - Injury caused by something external e.g. a sports injury.
• Slipped epiphysis - where the growing section of a bone at the end of a long bone slips and moves on the bone, which can cause a lot of pain.

In younger children the same symptoms could indicate, amongst other conditions:

• Osteomyelitis - an infection of the bone.

As the symptoms are general and could be caused by other conditions, many patients struggle to get a correct diagnosis when they first see a doctor. Many patients experience pain that is intermittent, and this can mislead doctors into thinking that the cause of the pain is temporary. Most patients do not actually feel ill until the cancer is fairly well advanced.

In addition, because most Ewing sarcoma patients are in their teens, the pain is sometimes mistaken for bone growth or 'growing pains'. Patients in this age group are also usually very physically active and the pain may be suspected to be from a sports injury or everyday activities.

Clinical signs:

• A mass that can be felt (palpable) when undergoing physical examination.
• Broken bone (fracture) resulting from weakening of bone due to a tumour, this is known as a 'pathological fracture.'

Going to the doctor

People report a variety of experiences when they seek medical advice about their symptoms. Most people with worrying symptoms go to their General Practitioner (GP).

Some people are referred quickly for further tests or a second opinion, but often patients have to return to their GP three or four times before they are referred for more tests. Primary bone cancers are very rare and many GPs will never come across a case.

The symptoms of Ewing sarcoma are general. There is no one clear sign that doctors can easily look for to make a diagnosis of Ewing sarcoma.

One of the main symptoms is pain. GPs sometimes suspect this of being 'growing pains' or a sports injury at first. This is probably because most people with osteosarcoma are between 10 and 24 years old, and this is an age when a lot of people take part in sports.

Another condition that GPs sometimes misdiagnose from the symptoms of Ewing sarcoma is Osgood Schlatters disease. This condition is found in physically active adolescent boys and girls, and is caused by stress on the tendons that connect to the knee-cap. This also causes pain in the leg bones, similar to Ewing sarcoma.

The Bone Cancer Research Trust is trying to find ways to make the time between the start of symptoms and getting the diagnosis much shorter. This is not a simple task and currently there is only a small amount of research on the subject. However, we are participating in a national project to look at ways of reducing the length of time it takes to reach a diagnosis. We have also partnered with the Royal College of GPs to provide an online learning module to help GPs to diagnose primary bone cancers.

Some patients go to their local hospital emergency department (A&E) or other health care centres. There is no scientific evidence available to examine whether patients presenting to their A&E are diagnosed any faster than patients who go to their GP. This is also an area where research is needed.

If a GP or doctor is concerned about the patient's symptoms, there are national guidelines that they should follow:

According to the National Institute for Clinical Excellence (NICE) guidelines for suspected bone cancer and sarcoma:

• If a primary healthcare professional has concerns about the interpretation of a patient's symptoms and/or signs, a discussion with the local specialist should be considered.
• A patient who presents with symptoms suggesting bone cancer or sarcoma should be referred to a team specialising in the management of bone cancer and sarcoma, or to a recognised bone cancer centre, depending on local arrangements.
• Patients with increasing, unexplained or persistent bone pain or tenderness, particularly pain at rest (and especially if not in the joint), or an unexplained limp should be investigated by the primary healthcare professional urgently.
• A patient with a suspected spontaneous fracture should be referred for an immediate X-ray. If a GP suspects primary bone cancer, they will normally ask for an x-ray of the bone and refer a patient for a specialist opinion, usually at a local hospital. They may also ask for some blood tests to look at the patient's general health.

Again, according to the National Institute for Clinical Excellence (NICE) guidelines for suspected bone cancer and sarcoma:

• If an X-ray indicates that bone cancer is a possibility, an urgent referral should be made.
• If the X-ray in normal but symptoms persist, the patient should be followed up and/or a repeat X-ray or bone function tests or a referral requested.

The guidelines state that if a primary healthcare professional is worried about any symptoms that could indicate primary bone cancer, they should ask a local specialist for advice. It may be more useful for the primary healthcare professional to contact a specialist at a bone cancer centre, where the staff are more used to diagnosing primary bone cancer.

If the x-ray shows that that the patient may have a primary bone cancer, then more tests are necessary. Some of these may also be done in a local hospital but patients should be referred to a Bone Cancer Centre early on during the process for the completion of these tests.

Going to a Bone Cancer Centre for more tests

Once an abnormality is found in a bone that suggests the possibility of cancer, the patient will be referred to a Bone Cancer Centre.

Bone Cancer Centres are specialist hospital centres. They have a group of healthcare specialists who are experts in the diagnosis and treatment of bone cancer.

In England, there are currently five Bone Cancer Centres, which specialise in the diagnosis and treatment of primary bone cancers. These centres are at Birmingham, Newcastle, Oswestry, Oxford, and Stanmore.

In the Republic of Ireland, there are no specific Bone Cancer Centres. Patients are initially seen in their local hospital and subsequently referred to specialist hospitals in Dublin or Cork for further tests and, if necessary, for treatment.

Patients in Wales usually travel to Oswestry or Birmingham for these specialist tests.

In Scotland there are five sarcoma centres and so patients travel to one of these centres for diagnosis if primary bone cancer is suspected. These centres are in Edinburgh, Glasgow, Inverness, Aberdeen and Dundee.

In Northern Ireland, patients are usually seen in Belfast.

For a full list of locations patients may be referred to in order to confirm a primary bone cancer diagnosis please click here

Multidisciplinary teams

Specialists in many different areas of medicine at hospitals in Ireland and at Bone Cancer Centres and the Regional Cancer Centres in the UK work together as a 'Multidisciplinary Team' (MDT). The members of the Multidisciplinary Team work together to diagnose the patient's condition.

The MDT who will look after the patient during investigation (tests) and diagnosis will include:

• Specialist bone sarcoma surgeons.
• Specialist sarcoma oncologists (oncologists are doctors that look after people with cancer).
• Specialist sarcoma pathologists (pathologists are doctors that use laboratory techniques to diagnose disease).
• Radiologists (doctors that diagnose disease and conditions from looking at x-rays, or scans).
• Sarcoma cancer nursing specialists (sometimes called 'CNS') perform an essential role in treating and caring for primary bone cancer patients.

What tests are done?

When a person is referred to a Bone Cancer Centre, further tests will be done to find out more and to confirm whether the patient has bone cancer, and if so what kind of tumour it is.

X-rays are taken of the bone, including the joints above and below, and the radiographs (x-ray pictures) are studied. These x-rays may show swelling around the bone or areas of abnormal bone growth. A chest x-ray is sometimes taken to show whether the cancer has spread to the lungs.

Cancer Research UK gives more information about x-rays.

Blood tests involve taking a small sample of blood from a vein using a needle. The sample of blood is tested in laboratories to check a patient's general health and for levels of certain substances or chemicals in the blood. These include:

Blood chemistry (Urea and Electrolytes) is checked to examine the levels of normal salts and urea and creatinine, which are waste products. This test can give clues to how well the kidneys are working

Full blood count (FBC) counts the numbers of different types of blood cells in the patient's blood at that time. These include:

• Red blood cells - which carry oxygen in the blood.
• White blood cells - which are essential to the immune system (and totals of each type).
• Platelets - which are essential to the making blood clots and scabs.
• Levels of haemoglobin - which is found in red blood cells.
• Liver function tests (LFTs) to see how the liver is working.
• Erythrocyte Sedimentation Rate (ESR) is a test to look for signs of inflammation.
• C-Reactive Protein (CRP) levels are tested as CRP levels increase in inflammation.
• Alkaline phosphatase (ALP) levels are measured in patients with suspected osteosarcoma.

Cancer Research UK gives more information about blood tests.

• MRI scan
  MRI stands for 'magnetic resonance imaging'. This type of scan is similar to a CT scan but magnetism and radio waves are used instead of x-rays to build up a very detailed 3-dimensional image.An MRI scan of the entire bone is used to gain more information about the tumour in the bone.The scanner is doughnut shaped; there is a short tunnel, which a motorised bed moves through during the scan. The MRI scanner can be quite noisy - some machines have a CD player so that patients can listen to their choice of music during the scan.Sometimes an injection of a special dye, known as a contrast agent may be needed. This makes certain tissues show up more clearly and with greater detail on the scan. The results of the scan will be examined by a radiologist and a report will be produced.
  Cancer Research UK gives more information about MRI scans.
• CT scan
  CT stands for 'computerised tomography'. They may also be called CAT scans, which stands for 'computerised axial tomography'.The scanner takes x-rays from many different angles and a computer builds up a 3-dimensional picture of the body in great detail. The pictures show cross-sections of the inside of the body.CT scanning of the lungs shows up any secondary tumours where the cancer may have spread (metastases). It is used if the MRI scan results have not been able to confirm the diagnosis of osteosarcoma. CT scans are also used to help doctors understand more about the exact location and size of the bone tumour.A CT scanner looks like a large doughnut with a bed for the patient to lie on. The bed moves slowly through the hole of the doughnut while the machine takes the pictures.Before the scan, patients may be given a contrast medium - usually injected into a vein. This helps to improve the image of some particular tissues, and it can also help the radiologist tell the difference between blood vessels and other structures.The results of the scan will be examined by a radiologist and a report will be produced.
  Cancer Research UK gives more information about CT scans.
• Bone scan
  Bone scans are used to look for abnormalities in bones. Patients who have a suspected primary bone cancer will sometimes have a full body bone scan. Scans are usually carried out in hospital nuclear medicine departments.A tiny amount of harmless radioactive substance (radionuclide) is injected into the patient's blood, which is then taken up by the bones fairly quickly (~2-4 hours).During the scan the radioactivity is detected by a specialised camera called a gamma camera.
  The radioactivity will collect more at areas of high activity (breakdown and repair) in the bone. The areas of high activity picked up by the gamma camera are known as 'hot spots'. These areas can be caused by a tumour. Patients will need to drink lots of fluids before the scan to help the radioactive substance travel to the bones quickly. The scanner looks like a bit like a CT scanner (doughnut shape). Patients lie on the bed, which travels through the doughnut. The results of the scan will be examined by a radiologist who will write the results in a report, which may take a few days to produce. Following the scan, the radionuclide will be passed completely from the body in the urine within 24 hours.
  Cancer Research UK gives more information about bone scans.
• PET scan
  PET stands for 'positron emission tomography.' Not all hospitals have PET scanners but they are increasingly being used in the diagnosis of cancer.PET scans can examine the whole body, rather than a specific area. They can also detect how well treatments are working.Before the scan, a small injection of radioactive glucose (a radiotracer) called fluorine18 will be given. Glucose is the fuel that cells use for energy. Cells that are very active such as cancer cells will take up more of this radioactive glucose than less active cells.The tracer will take around an hour to spread around the body. During the scan, which can last about an hour, the patient lies on a bed and the scanner passes over them. The scanner detects where the radiation is concentrated and produces images.When the body breaks down the radioactive glucose, particles called 'positrons' are released or emitted, the PET scanner detects the energy from the positrons and shows up as a 3-D image on a computer screen. Areas of high positron concentrations show up as a different colour and brightness on the image compared to areas of low positron concentration.The results of the scan will be examined by a radiologist.
  Cancer Research UK gives more information about PET scans.
• Biopsy
  A bone biopsy is a specialised procedure that should only be performed by a specialist in orthopaedic surgery or sarcoma radiology at a Bone Cancer Centre. A biopsy is usually performed by the same surgeon who will operate on the patient's cancer. Alternatively it can be performed by a specially trained radiologist. A biopsy involves taking a small sample of a lump or tumour so that a pathologist can examine the cells in the sample and determine whether the lump is cancerous or not. The biopsy sample can be taken using a needle, which is called a 'needle biopsy', or with a small operation, often referred to as an 'open biopsy'. In both cases, a small amount of the lump is taken. Sometimes a scan is performed at the same time to make sure that the biopsy is taken from the right place. The biopsy is studied by a pathologist who can do different tests to work out what type of cells are in the sample, this is a process known as 'histology'. This takes time and so the results of a biopsy can take a week or more
• Cancer Research UK gives more information on bone biopsies.
• Bone marrow biopsy
  All patients with Ewing sarcoma will have a bone marrow biopsy and aspirate taken to see whether the Ewing sarcoma may have spread to the bone marrow.
  Cancer Research UK gives more information on bone marrow tests.

What other diagnoses might be made if it's not Ewing sarcoma?

The biopsy enables doctors to be certain whether a patient has Ewing sarcoma. This is important because other conditions can look like Ewing sarcoma on x-rays and scans. This is known as a differential diagnosis.

Other possible conditions can include:

• Eosinophilic granuloma - a benign (non-cancerous) bone tumour that is found mainly in children under the age of 10 years.
• Lymphoma - a blood cancer that can cause bone destruction.
• Acute osteomyelitis - bone damage caused by an infection inside the bone.
• Chronic osteomyelitis - a more serious form of this bone infection.
• Osteosarcoma - a different kind of primary bone cancer.
• Chondrosarcoma - a different kind of primary bone cancer, which develops in the cartilage. Cartilage protects the outside of the bones.

At this point, most patients will be referred to their Regional Cancer Centre where treatment will start. This should be a specialist sarcoma centre or children's and young people's cancer centre.

Who is involved in deciding the treatment for Ewing sarcoma?

Specialists in many different areas of medicine at hospitals in Ireland and at Bone Cancer Centres and the Regional Cancer Centres in the UK work together as a 'Multidisciplinary Team' (MDT). The Multidisciplinary Team will work out the details of the treatment needed.

The MDT at the investigation (tests) and diagnosis stage will consist of:

• Specialist bone sarcoma surgeons
• Specialist sarcoma oncologists (oncologists are doctors that look after people with cancer)
• Specialist cancer nurses
• Specialist sarcoma pathologist (pathologists are doctors that use laboratory techniques to diagnose disease)
• Radiologists (doctors that diagnose disease and conditions from looking at x-rays, or scans)

Patients who are having treatment for Ewing's sarcoma will be under the care of the treatment and rehabilitation part of the multidisciplinary team including:

• Specialist bone sarcoma surgeons
• Specialist sarcoma oncologists (oncologists are doctors that look after people with cancer)
• Specialist cancer nurses
• Physiotherapists and occupational therapists will help with rehabilitation (rehab) after surgery
• Dieticians
• Social workers and psychologists will help with patients' emotional, social and educational needs

Where will treatment take place?

Treatment for Ewing sarcoma can take place at different hospitals around the UK and Ireland. For patients whose nearest specialist hospital is too far away, a 'shared care' arrangement with a closer hospital might be set up. This means that the specialist hospital recommends a treatment plan, which is used to treat the patient at a hospital closer to home.

England and Wales

Diagnosis and surgery should take place in one of the five Bone Cancer Centres (see the map below):

• North of England Bone and Soft Tissue Tumour Service (Newcastle upon Tyne Hospitals NHS Foundation Trust)
• Nuffield Orthopaedic Centre NHS Trust (Oxford)
• Royal National Orthopaedic Hospital (Stanmore, Middlesex)
• The Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust (Oswestry)
• The Royal Orthopaedic Hospital, Bristol Road South (Northfield, Birmingham)

Scotland

Patients are treated at one of the five Sarcoma Centres that are part of the Scottish Sarcoma Network. These hospitals are in Aberdeen, Dundee, Edinburgh, Glasgow, and Inverness. Patients visit one of these five Sarcoma Centres for chemotherapy or radiotherapy treatment. For surgery, primary bone cancer patients are seen in Glasgow, Edinburgh or Aberdeen.

Republic of Ireland

Most patients aged under 16 receiving chemotherapy for Ewing sarcoma are treated at Our Lady's Hospital, Crumlin, Dublin.

Patients aged 15-19 are treated at Mater Misercordiae Hospital, Our Lady's Hospital, Crumlin and Waterford Regional Hospital.

Patients aged over 20 are treated at Mater Misercordiae Hospital, Our Lady's Hospital Crumlin, Sligo General Hospital, Cork University Hospital, Waterford Regional Hospital, St Vincent's Hospital and Mercy Hospital.

For surgery, most patients in the Republic of Ireland (all ages) go to St. Marys Orthopaedic, Cappagh. For radiotherapy most patients attend St Luke's and St Anne's Hospital, Dublin. However, some patients may also attend other hospitals in Dublin and Cork.

Key

Red stars: Specialist Children's Cancer and Leukaemia Centre
Blue stars: Bone Cancer Centre
Green stars: Children and Young People's Integrated Cancer Service
Purple stars: Teenage Cancer Trust Unit
Yellow stars: Scottish Sarcoma Network Hospital

Please see our full list of centres providing treatment for primary bone cancer here.

What kind of treatment is used for Ewing sarcoma?

Treatment for Ewing sarcoma involves treatment to the whole body with chemotherapy (systemic therapy), and treatment of the tumour site with surgery and radiotherapy (local therapy).

Each Ewing sarcoma patient has a slightly different treatment plan, depending on the stage of their disease and where in their body the cancer started.

Your doctor (oncologist) is the best person to describe to you the treatment choices. Your doctors will also tell you what is to be expected from the treatment.

Treatment of cancer involves patients and the doctors working together to find a care or treatment plan that fits your needs.

Treatment: Overview

Following the diagnosis and the first tests, patients are given a combination of chemotherapy drugs before surgery. The number of drugs, how long they are given for and how many times they are given varies from country to country.

In the UK and Ireland, the standard treatment is to give the patient a series of different treatments, usually in this order:

• Chemotherapy to shrink the tumour
• Surgery to remove the tumour
• Radiotherapy to kill any remaining tumour cells
• Chemotherapy to kill any cancer cells that might have escaped from the tumour
• Follow-up monitoring to make sure the cancer has gone.

Chemotherapy given before surgery is called neo-adjuvant chemotherapy. The aim of this course of chemotherapy is to shrink the primary tumour, and to kill any cells that have spread to other parts of the body.

Following a number of cycles of chemotherapy, the main tumour site is treated. Where possible this means that the patients have surgery to remove the primary tumour. This is more likely to be possible if the main (primary) tumour is in a limb (arm or leg) or easily accessible position in the body. For many patients the main tumour is not easily removable, for example, if the tumour is in the pelvis or spine.

When the tumour is removed, it is examined under a microscope by the pathologist, to make sure that the tumour has been completely removed and to find out how much of the tumour has been killed. The results of this examination may affect treatment after surgery.

After surgery, radiotherapy is given if:

• Not all the tumour is completely removed.
• More than 10% of the tumour is still alive when examined under a microscope.

The exact dose and length of radiotherapy treatment will also be decided by a special team of doctors, but it is usually given as a single dose each day (a few minutes) for approximately 5 – 6 weeks.

Chemotherapy will usually continue after surgery (this is called adjuvant chemotherapy), and will be given during any radiotherapy treatment that the patient requires. This makes sure that any cancer cells that could have escaped from the primary tumour. are killed before they have a chance to grow into new tumours.

At diagnosis, 25-30% of patients have evidence that their cancer has spread to the lungs, other bones, or to the bone marrow.

If there is evidence that the tumour has spread to other parts of the body then an oncologist and surgeon may consider removing the secondary cancers by surgery.

Treatment: In Detail

Chemotherapy before surgery (Neo-Adjuvant Chemotherapy)

In the UK, Ireland, and much of Europe the current standard treatment before surgery is made up of four chemotherapy drugs, which are given together: Vincristine, Ifosfamide, Doxorubicin, Etoposide (this is sometimes called VIDE). The combination of chemotherapy drugs is sometimes called a 'protocol' or 'regimen'.

Drugs are given in a combination in order to maximise their effect. If the cancer stops responding to one of the drugs then the aim is that the other drugs will still be effective in killing the cancer cells.

Each course of these four drugs is given over 3-4 days every 3 weeks (1 cycle) for 6 cycles. This takes about 18 weeks in total.

Chemotherapy may be given as part of a 'clinical trial' (this is a study used to investigate new or different treatments or side effects of treatments).

In some patients, chemotherapy is given to help slow down the growth of the tumour and decrease symptoms when their cancer is advanced and unable to be cured. This is known as 'palliative chemotherapy.'

Types of chemotherapy drugs used to treat Ewing sarcoma are:

• Doxorubicin
• Etoposide
• Vincristine
• Actinomycin D
• Cyclophosphamide
• Ifosfamide
• Temozolamide
• Irinotecan

Surgery

The decision about whether surgery is possible is usually taken by the multidisciplinary team, which includes expert surgeons.

The aim of surgery is to remove the primary tumour safely and at the same time try to keep the body working as normally as possible.

If the primary tumour is in a limb then it is usually possible to remove the tumour without removing the limb.

Surgeons have developed different surgical techniques to remove bone tumours whilst preserving the function of the limb. The main technique is replacement of the affected bone with a metal implant and false joint. Another technique is to carry out an autologous (aw-TOH-low-gus) bone graft in which a piece of healthy bone is taken from the patient to replace the bone that has been damaged by a tumour.

Other surgical techniques include resection alone (where just the tumour is removed), allografts (where donated tissue is used to rebuild the limb) and irradiation/ re-implantation, which is where the bone that contains the tumour is removed and treated with radiation. This kills any tumour cells inside the bone, and so the bone can be safely put back into the patient.

Despite these advances in surgical techniques around 10% of patients require an amputation (removal of the limb) to safely remove the tumour. Wherever possible a prosthetic (artificial) limb can be made for the patient. Amputation may also be needed if the cancer has spread to major blood vessels or nerves or if the patient develops a bad infection or other serious complications after limb-sparing surgery

Surgery to remove tumours that are not in the limbs, for example tumours that are in the pelvis, spine and skull, can be very complicated and requires very careful individual planning for each patient.

When compared with other bone tumours, Ewing sarcomas respond well to radiotherapy. Sometimes when surgical removal is not possible, radiotherapy can be used alone to kill the cancer cells at the primary tumour site.

Surgery may also be used to remove secondary tumours, such as tumours in the lungs.

Surgery may be needed in future if the reconstruction of the limb wears out or if the tumour comes back.

Radiotherapy

Radiotherapy is a type of 'local therapy', meaning that it is designed to treat the tumour and not the whole body. Radiotherapy involves using a focussed beam of energy to kill the cancer cells that make up the tumour.

The energy used in radiotherapy is a high-energy form of X-rays. The energy beam damages the DNA inside the cancer cells inside the tumour, and this DNA damage prevents the cells from dividing, and causes the cells to die.

Radiotherapy is administered by a radiation oncologist. Radiotherapy is usually given as a single dose each day (a few minutes) for approximately 5 – 6 weeks.

Radiotherapy is sometimes used instead of surgery, in cases where surgical removal of the primary tumour is not be possible, for example if the tumour is in the pelvis or spine. Radiotherapy may also be used after surgery if not all the tumour is completely removed or more than 10% of the tumour is still alive when examined under a microscope.

Patients who receive radiotherapy may experience unpleasant side-effects from this treatment. These side effects can include:

• Sore skin
• Tiredness
• Dry mouth and difficulty swallowing
• Feeling sick, loss of appetite
• Diarrhoea
• Hair loss

Chemotherapy after surgery (Adjuvant Chemotherapy)

Once again, the number of drugs and length of treatment may be different from country to country. Most treatment courses last for a further 8 cycles over about 24 weeks after surgery.

In the UK, Ireland and much of Europe the current standard chemotherapy treatment after surgery is made up of the four drugs (Vincristine, Actinomycin D, Ifosfamide, Cyclophosphamide) and lasts for 24 weeks after surgery, (VAI for 1 cycle, VAC for 7 cycles). Chemotherapy given after the surgery is known as adjuvant chemotherapy.

How chemotherapy works

Often called chemo (key-mo) for short, 'chemotherapy' is the name for drugs used for the treatment of cancer. These drugs kill cancer cells or stop their growth by interfering with the way cells divide and grow (also known as the cell cycle), or by damaging the cell's DNA (instructions).

Cancer cells are different to healthy cells because the cancer cells divide very rapidly. This fact is exploited by chemotherapy drugs, which target only rapidly dividing cells. Different chemotherapy drugs achieve this by targeting slightly different parts of the machinery that makes cells divide, and so often these different drugs are used together in combinations, to hit different parts of the cancer cell at the same time. This is called combination chemotherapy.

Most healthy cells do not divide very rapidly. However, some types of healthy cell do divide rapidly, and these include hair follicle cells, skin cells, bone marrow cells, and the cells lining the digestive system. This means chemotherapy drugs can also affect these healthy quick-dividing cells and this is what causes the side effects that are associated with chemotherapy treatment.

Side effects can be unpleasant, such as nausea, diarrhoea, hair loss, mouth sores, an unusual taste in the mouth and tiredness (fatigue). Medications can be given before and after chemotherapy to help with some of these side effects.

There are tips on some good websites about dealing with side effects:

• Coping with hair loss: Teenage Info on Cancer (TIC) and Teenage Cancer Trust
• Mouth sores and eating problems: Teenage Cancer Trust and TIC and Macmillan
• Former osteosarcoma patient, Megan Blunt, has written a book filled with tips on how to cope with chemotherapy. It's called Chemotherapy, Cakes and Cancer is available to download as a PDF published by CLIC Sargent.

How is chemotherapy given?

There are different ways patients are given chemotherapy: tablets, liquid medicine, injection or directly into the blood. When a patient is given chemotherapy directly into their blood, the drug is given through a cannula (venflon), which is a flexible thin plastic tube that sits in a vein in the arm or hand. Alternatively, patients may have a central line, PICC (peripherally inserted central catheter) or implantable ports (Portacath®).

Portacaths®, PICCs and central lines can be kept in for weeks or even a few months. These lines enable the number of needles required during treatment to be minimised and more than one drug or treatment (such as fluids or nutrition) can be given at the same time because the lines can have multiple openings or 'lumens'.

Because central lines, PICCs and Portacaths® are all slightly different; the decision on which type of line will best suit the patient will be discussed by the nurses and the doctor in the medical team.

Figure 1(a). A central line, also known as a Hickman line.

Image Courtesy of The Christie NHS Foundation Trust.

Figure 1(b). Peripherally Inserted Central Catheter (PICC).

Image Courtesy of The Christie NHS Foundation Trust.

Figure 1(c). Implantable Port, (Portacath©)

Image Courtesy of The Christie NHS Foundation Trust.

The chemotherapy drugs enters the blood through the cannula by an infusion usually called a drip. An infusion or drip is a method of giving a set amount (dose) of I.V. (IntraVenous) medications such as chemotherapy over a set period. This period can be hours or days. The infusion can also be controlled by an infusion pump, which is connected to a central line or a PICC line. Some of the pumps are small enough to fit in a pocket meaning that patients can use them at home.

Chemotherapy is given in 'cycles.' A cycle is the treatment time plus a resting time. For example, a patient may be given a combination of chemotherapy drugs over 3-4 days and then there may be a resting period of 2½ weeks. Therefore, the cycle is 3 weeks long. The resting period helps the healthy cells of the body to recover before the next treatment cycle begins.

High dose chemotherapy with autologous stem cell transplant

Some Ewing sarcoma patients may be offered high dose therapy with an autologous stem-cell transplant. Stem cells are the 'master cells' of the body, they are able to divide many times to make specialised cells that can replace damaged cells in the body. An 'autologous stem cell transplant' is when a patient's own stem cells are collected from their blood, and then stored safely until they are given back to the patient after treatment.

This treatment allows the chemotherapy drugs to be used at a very high dose so that they have the highest possible impact on the cancer. The doses of chemotherapy drugs are so high that they cause serious damage to the cells in the blood, including the red blood cells that carry oxygen and the white blood cells which protect the body from infection. These cells can be replaced by the stem cells that are given back to the patient after treatment.

High dose chemotherapy with autologous stem cell transplant follows this treatment plan:

• Stem cell harvest
  • Patients are given daily injections (Granulocte-Colony Stimulating Factor) in the run-up to the stem cell harvest. G-CSF is a molecular signal that encourages the production of more stem cells in the blood.
  • A blood test is done to test whether the numbers of white blood cells have increased and that the stem cells have moved from their usual home in the bone marrow, into the blood.
  • To carry out the harvest an apheresis catheter (a bit like a central line) is inserted into a large vein (either the top of the leg or the neck) in the operating theatre.
  • The catheter is linked by two lines to a machine called a cell separator. Blood from the patient passes though one line, into the cell separator. The stem cells are separated out from the blood and the cells are collected in a bag attached to the machine. The patient's blood is then returned to the patient through the second line. The blood in the cell separator is treated with a drug called ACD-A to prevent it from clotting. This drug can have some side effects.
  • The number of stem cells collected in the bag will be counted. If there are too few stem cells, the procedure will be repeated the next day.
  • The aphresis catheter is removed when the harvest is complete.
  • The harvested stem cells are frozen and carefully stored until it is time to give the cells back to the patient.

• High dose chemotherapy
  • The drugs used for high dose therapy are either Busulphan in combination with melphalan; or treosulphan in combination with melphalan (the second combination has less toxicity and so it is given to patients who have already experienced toxicity from previous treatment such as radiotherapy).
  • The high-dose drugs are given over the course of five days. After this there is a day's rest before the stem cells are re-infused.

• Autologous stem cell transplant
  • One day after the high-dose therapy has finished, the patient's stem cells are infused back into the patient, using a drip.

Patients usually stay in hospital for three to four weeks, as it takes some time for the blood cells to recover. The levels of white blood cells usually get back to normal in around two weeks, but the platelet count can take a bit longer.

Complementary or alternative medicines (CAM)

Although complementary and alternative medicines are often called 'CAM' for short as if they mean the same thing, there are differences between them.

Other names you may see to describe CAMs are:

• traditional medicines
• unconventional medicines
• integrated healthcare/medicine

Alternative medicines or therapies, such as extract of mistletoe (iscador) and laetrile (bitter almonds), are used instead of what are called 'conventional medicines'. Conventional medicines for cancer are the treatments prescribed by doctors, for example, chemotherapy and radiotherapy.

Some people may choose to stop taking conventional medicines because they may no longer be working, or they may not wish to begin their treatment using conventional medicines for many different reasons. However, alternative medicines do not have to go through the very careful testing (trials) that conventional medicines do, and therefore may not be safe.

Adverts for alternative medicines on websites may claim to cure cancer. However, there is no scientific evidence to back these claims up. It is always best to talk to an oncologist if people are thinking about trying alternative therapies.

Complementary medicines are used alongside conventional medical treatment. Some patients use complementary medicine to help with symptoms or to aid relaxation.

Techniques used by some Ewing sarcoma patients include:

• Acupuncture
• Massage therapy
• Herbal products
• Vitamins* or special diets*
• Visualization
• Meditation
• Spiritual healing.

* Patients should make sure they tell their doctors about any supplements they may be taking. Some complementary medicines, such as antioxidants, may interfere with conventional treatments.

Prognosis

The word 'prognosis' refers to what doctors think the chances are of the patient's cancer being cured with treatment or the likelihood of it returning. This depends on many different things, which vary between different patients.

In general, the prognosis for Ewing sarcoma depends on:

• The patient's age and general health
• The location and size of the Ewing sarcoma
• Results of investigations; the stage of the Ewing sarcoma, whether it is localised or metastatic (spread), or recurrent (come back)
• How much of the cancer could be removed by surgery
• Response to treatment, for example, how effective was chemotherapy prior to surgery
• Whether lung (pulmonary) metastases can be removed with surgery (resectable)

Doctors cannot be certain about a patient's prognosis as each patient and each cancer can behave differently.

The overall 5-year survival rate for Ewing sarcoma is around 60%. The term 5-year survival rate can sound quite misleading and worrying to some people. The term does not mean people only lived for 5 years after diagnosis; it refers to the fact that 60 out of every 100 people with Ewing sarcoma are alive 5 years after their diagnosis. These people may not all be cured; some may be still be undergoing treatment.

Follow-up care

After finishing treatment, Ewing sarcoma patients will require follow up care. Outpatient hospital visits will be needed on a regular basis for the first few years after treatment and then probably yearly after that.

These visits will help to keep an eye on a patient's general health as well as an opportunity to carry out some tests. These tests are very important because they can show up any 'late effects' from the cancer treatment. Most centres encourage patients to get in touch if they have problems between appointments.

Follow up care with an orthopaedic surgeon also helps to look out for surgery-related complications and to make sure the limb is working well.

The Children's Cancer and Leukaemia Group (CCLG) provide useful information for children and their parents about what to expect once treatment is finished.

Reaching the end of treatment can bring about mixed emotions. The thought of having no more chemotherapy can be a cause for celebration, but this can be mixed with anxiety about the future - many emotional issues can arise surrounding the process of returning to a 'normal' life after cancer.

For adults who have had treatment for cancer, the issues can be more complex and include workplace and financial issues. Macmillan Cancer Care provides a wealth of useful information on living with and after cancer, which includes information and tips on a broad range of topics.

Relapse and metastasis

Relapse means that the cancer has returned. This can be in the same bone as the cancer originally appeared (local relapse) or the cancer can return in a different place, often in the lungs (metastasis).

If the cancer returns it will require more treatment. This will probably involve more chemotherapy and sometimes further surgery. The MDT will be able to advise you on which treatments are necessary.

Emotional effects

The experience of having cancer can be frightening and stressful, and so the emotional effects of cancer can be as severe as the physical effects.

The Children's Cancer and Leukaemia Group have produced a booklet for teenagers and young adults called After Cure which is full of helpful information for living well after having cancer.

Macmillan Cancer Care has some very useful pages for adults on coping with the emotional aspects of cancer.

What are late effects?

Late effects are problems from cancer treatments such as chemotherapy and radiotherapy that may show up weeks or months after treatment has finished.

Chemotherapy drugs target cancer cells but they can also damage organs and kill healthy cells. Monitoring patients during treatment and follow-up should identify problems at an early stage, and therefore recognising them should limit the possibility of serious effects occurring.

For more information about side effects and late effects, visit Cancer Research UK's page on cancer drugs.

Health Problems/ Late Effects from Treatment	Type of Chemotherapy Drug/Cancer Treatment
Renal/ Kidney problems (nephrotoxicity)	Ifosfamide
Heart problems (cardiotoxicity)	Doxorubicin, cyclophosphamide
Osteopenia (mineral loss from bone)	Radiotherapy
Fertility problems (more likely in males than females)	Ifosfamide, radiotherapy, vincristine,temezolamide, irinotecan, busulfan, melphalan, treosulfan
Numbness, tingling or weakness (Neurotoxicity), more likely in older adults	Ifosfamide
Liver problems (hepatotoxicity), very rare	Ifosfamide, radiotherapy with chemotherapy
Second malignancy (another cancer)	Ifosfamide, etoposide, cisplatin, doxorubicin, actinomycin D, radiotherapy, temezolamide

There has been a lot of research into the biology of Ewing sarcoma in recent years, in order to help us to understand what causes cells to become cancerous; however there are still many un-answered questions. Recent research has been moving our knowledge forward but only very slowly.

We do know that cells contain important information in their chromosomes called genes, which instruct cells on how to divide and grow normally. Damage to certain genes can cause a cell to behave differently and grow abnormally, which can then lead to development of cancer.

We know that almost all Ewing sarcoma patients share the same kind of gene damage, although we don't know what causes this damage to happen.

Genes are made of a molecule called DNA. In cells, DNA is found in long strings called chromosomes. Each chromosome is made up of thousands of genes, one after another. We know that in Ewing sarcoma there is a chromosomal translocation - this means that a part of a chromosome has broken off and stuck to the wrong chromosome, or sometimes there is a swap of sections of DNA between one chromosome and another.

Translocations put the genes in the wrong order along a chromosome and this can mean that genes are switched on and off wrongly, in a way that can cause cancer or other illnesses.

Chromosomes

In figure 1, you can see the chromosomes in a human cell. Humans have 23 pairs of chromosomes. Each pair contains 1 copy from the mother and one copy from the father (this is how we can inherit traits from both parents). One pair of chromosomes forms the 'sex chromosomes', and if a person has XY they are male or if they have XX they are female.

The chromosomes have are been given a number from 1 to 22 (the sex chromosomes are number 23). Chromosome 1 is the longest, 2 is slightly shorter, and so on to number 22, which is the shortest.

Figure 1. The full set of human chromosomes, which are long strings of DNA.

Figure 2 shows a microscope picture that shows the chromosomes as strings in the centre of a cell.
The study of chromosomes is carried out by scientists known as cytogeneticists (SY-tow-geh-NET-eh-sist).

Figure 2. Microscope image of cells showing visible chromosomes inside the cells.

Chromosome translocations

In around 95% of Ewing sarcoma cases, there is a translocation between chromosomes, and we know that this translocation causes the cancer to start.

The particular translocation in Ewing sarcoma, PNET and Askin tumour is usually where a part of chromosome 11 has moved to chromosome 22 and a piece of chromosome 22 has moved to chromosome 11.

You may see this written as t(11;22)(q24;q11) when you are reading about Ewing sarcoma. The 't' stands for translocation and the numbers in the first brackets tell us which chromosomes are involved. The second bit in brackets tells us what part of the chromosome is involved. Some Ewing sarcoma patients have slightly different genetic changes. These are the translocations described as t(21;22)(q22;q12), t(7;22), t(17;22) or t(2;22) or a slightly different genetic change called inv(22).

How do chromosome translocations cause problems in cells?

When a translocation occurs, it interferes with the genes. Genes can be broken when the chromosomes break, so the genes can't do their usual job in the cell. Alternatively, two genes can be stuck together where the chromosomes join together. This fuses two genes together, making a so called 'fusion gene', which has some properties of each gene. Either of these situations can cause cancer.

In the case of Ewing sarcoma the translocation between chromosomes 11 and 22 joins two genes together, one called EWS and the other called FLI1, to form a 'fusion gene' called EWS-FLI1. Fusion genes are found in different cancers but EWS-FLI1 is specific to the Ewing sarcoma Family of Tumours and can therefore help to confirm the diagnosis of Ewing sarcoma.

The formation of the EWS-FLI1 fusion gene instructs the cell to make EWS-FLI1 fusion protein, which is a 'transcription factor'. Transcription factors are powerful switches in the cell, able to switch many other genes on or off. EWS-FLI1 causes cancer by switching the wrong genes on and off at the wrong times, causing the cell to divide uncontrollably.

The EWS-FLI1 translocation happens only in the cells of the tumour. The translocation does not occur in sperm or egg cells and therefore people with Ewing sarcoma can't pass the translocation on to their children. This means that there is no increased risk of Ewing sarcoma for the children of surviving patients. There is also no increased risk for brothers and sisters of Ewing patients.

Why is research into the biology of Ewing sarcoma important?

Research to identify the exact cell type in which the EWS-FLI1 translocation happens and Ewing sarcoma starts is a big area of research. Knowing this could allow scientists and doctors to work out what causes the chromosome translocations to happen.

Understanding the biology of cancer cells helps doctors and scientists to find new targets for treatment and markers (clues) that can help a patient to be diagnosed quicker. For example, some researchers are trying to make new drugs that target EWS-FLI1 fusion protein, to allow all Ewing sarcoma cells to be killed without harming healthy cells.

The Bone Cancer Research Trust's information has been compiled using only peer-reviewed clinical and scientific studies, reviews and case studies. Peer-review is a process in which the work of one scientist or doctor is looked at and checked by other experts in the same subject area. The peer-review process helps ensure the science is 'reliable'.

If you are interested in reading deeper into the subject, we have provided a bibliography listing the references and books we used to compile our information about Ewing sarcoma.

Books

• Alberts B, Johnson A, Lewis J, Raff M. Molecular Biology of the Cell. Garland Science; 5th edition, 2005. ISBN-10: 0815341059.
• Cullinane CJ, Burchill SA, Squire JA, O'Leary JJ, Lewis IJ (eds). Molecular Biology and Pathology of Paediatric Cancer. Oxford University Press. ISBN-10: 0192630792.
• Kleihues P, Sobin L, Fletcher C et al, (eds.) WHO Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone, Lyon, France: IARC Press. PDF version download (free)
• Mackay J. The chemotherapy and radiotherapy survival guide. New Harbinger Publications, 1998. ISBN 1572240709.
• Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available to download here.

Ewing sarcoma: general

• Balamuth NJ, Womer RB. Ewing's sarcoma. The Lancet Oncology, 2010; 11( 2): 184 - 192.
• Bernstein M, Kovar H, Paulussen M, Randall RL, Schuck A, Teot LA, Juergens H. Ewing's sarcoma family of tumors: current management. Oncologist. 2006; 11(5): 503-19. Free full text available from: Free full text available here.
• Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from here.
• Ewing J. Diffuse Endothelioma of Bone. CA Cancer J Clin. 1972; 22; 95-98. Free full text available here.
• Ewing, J. Diffuse Endothelioma of Bone. Proc. N. Y. Path. Soc. 1921; 7(21): 17-24.
• Eyre R, Feltbower RG, James PW, Blakey K, Mubwandarikwa E, Forman D, McKinney PA, Pearce MS, McNally RJ. The epidemiology of bone cancer in 0 - 39 year olds in northern England, 1981 - 2002. BMC Cancer. 2010;10(1):357. [Epub ahead of print]. Free full text available from here.
• Eyre R, Feltbower RG, Mubwandarikwa E, Jenkinson HC, Parkes S, Birch JM, Eden TO, James PW, McKinney PA, Pearce MS, McNally RJ. Incidence and survival of childhood bone cancer in northern England and the West Midlands, 1981-2002. Br J Cancer. 2009; 100(1): 188-93.
• Jawad MU, Cheung MC, Min ES, Schneiderbauer MM, Koniaris LG, Scully SP. Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005. Cancer. 2009; 115(15): 3526-36.
• Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
• Koster H, Weintrob M. Diffuse Endothelioma of Bone: Ewing's sarcoma. Ann Sur. 1931; 94(1): 111-116. Free full text available from here.
• Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
• Lee YY, Kim do H, Lee JH, Choi JS, In KH, Oh YW, Cho KH, Roh YK. Primary pulmonary Ewing's sarcoma/primitive neuroectodermal tumor in a 67-year-old man. J Korean Med Sci. 2007; 22 Suppl:S1, 59-63. Free full text available from here.
• Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from here.
• Ludwig JA. Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr Opin Oncol. 2008; 20(4): 412-8.
• Maheshwari AV, Cheng EY. Ewing sarcoma family of tumors. J Am Acad Orthop Surg. 2010 Feb;18(2):94-107.
• Medline Plus. Medical encyclopaedia: Ewing's sarcoma. Accessed December 2009 from here.
• Ordóñez JL, Osuna D, Herrero D, de Alava E, Madoz-Gúrpide J. Advances in Ewing's sarcoma research: where are we now and what lies ahead? Cancer Res. 2009; 69(18):7140-50.
• Whelan J. Managing sarcomas in teenagers and young adults. Eur J Cancer Suppl, 2009; 7(2): 82.
• van den Berg H, Dirksen U, Ranft A, Jürgens H. Ewing tumors in infants. Pediatr Blood Cancer. 2008;50(4):761-4.
• van den Berg H, Heinen RC, van der Pal HJ, Merks JH. Extra-osseous Ewing sarcoma. Pediatr Hematol Oncol. 2009; 26(4): 175-85.

Ewing biology

• Avigad S, Shukla S, Naumov I, Cohen IJ, Ash S, Meller I, Kollender Y, Issakov J, Yaniv I. Aberrant methylation and reduced expression of RASSF1A in Ewing sarcoma. Pediatr Blood Cancer. 2009; 53(6): 1023-8.
• Bernstein M, Kovar H, Paulussen M, Lor Randall R, Schuck A, Teot LA, Jurgens H. Ewing's Sarcoma Family of Tumours: Current Management. The Oncologist. 2006; 11:503-519
• Burns JS, Abdallah BM, Schrøder HD, Kassem M. The histopathology of a human mesenchymal stem cell experimental tumor model: support for an hMSC origin for Ewing's sarcoma? Histol Histopathol. 2008; 23(10): 1229-40.
• Cancer Genetics Web. EWSR1; Ewing sarcoma breakpoint region 1 (22q12). Accessed November 2009 from here.
• Coles EG, Lawlor ER, Bronner-Fraser M. EWS-FLI1 causes neuroepithelial defects and abrogates emigration of neural crest stem cells. Stem Cells. 2008; 26(9): 2237-44. Free full text available here.
• Damron TA; Ward WG; Stewart A. Osteosarcoma, chondrosarcoma, and Ewing's sarcoma: National Cancer Data Base Report. Clin Orthop Relat Res. 2007; 459:40-47.
• Kauer M, Ban J, Kofler R, Walker B, Davis S, Meltzer P, Kovar H. A molecular function map of Ewing's sarcoma. PLoS One. 2009; 4(4): e5415. Epub 2009 Apr 30. Free full text available here.
• Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
• Kinsey M, Smith R, Iyer AK, McCabe ER, Lessnick SL. EWS/FLI and its downstream target NR0B1 interact directly to modulate transcription and oncogenesis in Ewing's sarcoma. Cancer Res. 2009; 69(23): 9047-55. Epub 2009 Nov 17. PMID: 19920188.
• Krishnan B, Khanna G, Clohisy D. Gene Translocations in Musculoskeletal Neoplasms. Clin Orthop Relat Res. 2008; 466(9): 2131-2146. Free full text available here.
• Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
• Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from here.
• Ordóñez JL, Osuna D, Herrero D, de Alava E, Madoz-Gúrpide J. Advances in Ewing's sarcoma research: where are we now and what lies ahead? Cancer Res. 2009; 69(18):7140-50.
• Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available from here.
• Romeo S, Dei Tos AP. Soft tissue tumors associated with EWSR1 translocation. Virchows Arch. 2009 Nov 20. [Epub ahead of print] PMID: 19936782.
• Riggi N, Stamenkovic I. The Biology of Ewing sarcoma. Cancer Lett. 2007; 254(1): 1-10.
• Riggi N, Suva ML, Stamenkovic I. Ewing's sarcoma origin: from duel to duality. Expert Rev Anticancer Ther. 2009; 9(8): 1025-30.
• Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from here.
• Yu M, Wan Y, Zou Q, Xi Y. High frequency of mitochondrial DNA D-loop mutations in Ewing's sarcoma. Biochem Biophys Res Commun. 2009; 390(3): 447-50.

Causes and risk factors

• Eyre R, Feltbower RG, Mubwandarikwa E, Eden TO, McNally RJ. Epidemiology of bone tumours in children and young adults. Pediatr Blood Cancer. 2009; 53(6): 941-52.
• Jawad MU, Cheung MC, Min ES, Schneiderbauer MM, Koniaris LG, Scully SP. Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005. Cancer. 2009; 115(15): 3526-36.
• Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
• Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
• Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from here.
• Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from here.

Presentation

• Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
• Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
• Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from here.
• Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available from here.
• Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from here.
• Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am. 2000; 82: 667-674.

Diagnosis

• Burchill SA. Ewing's sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol. 2003; 56(2): 96-102.
• Iwamoto Y. Diagnosis and Treatment of Ewing's sarcoma. Japanese Journal of Clinical Oncology, 2007; 37(2):79-89. Free full text available here.
• Kavalar R, Pohar Marinsek Z, Jereb B, Cagran B, Golouh R. Prognostic value of immunohistochemistry in the Ewing's sarcoma family of tumors. Med Sci Monit. 2009; 15(8): CR442-52.
• Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
• Kleis M, Daldrup-Link H, Matthay K, Goldsby R, Lu Y, Schuster T, Schreck C, Chu PW, Hawkins RA, Franc BL. Diagnostic value of PET/CT for the staging and restaging of pediatric tumors. Eur J Nucl Med Mol Imaging. 2009; 36(1): 23-36.
• Lee YY, Kim do H, Lee JH, Choi JS, In KH, Oh YW, Cho KH, Roh YK. Primary pulmonary Ewing's sarcoma/primitive neuroectodermal tumor in a 67-year-old man. J Korean Med Sci. 2007; 22 Suppl:S1, 59-63. Free full text available here.
• Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
• Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from here.
• Machado I, Noguera R, Pellin A, Lopez-Guerrero JA, Piqueras M, Navarro S, Llombart-Bosch A. Molecular diagnosis of Ewing sarcoma family of tumors: a comparative analysis of 560 cases with FISH and RT-PCR. Diagn Mol Pathol. 2009; 18(4): 189-99.
• Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available from here.
• Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from here.

Treatment

• Asami S, Chin M, Shichino H, Yoshida Y, Nemoto N, Mugishima H, Suzuki T. Treatment of Ewing's sarcoma using an antisense oligodeoxynucleotide to regulate the cell cycle. Biol Pharm Bull. 2008; 31(3): 391-4.
• Bacci G, Palmerini E, Staals EL, Longhi A, Barbieri E, Alberghini M, Ferrari S. Ewing's sarcoma family tumors of the humerus: outcome of patients treated with radiotherapy, surgery or surgery and adjuvant radiotherapy. Radiother Oncol. 2009; 93(2): 383-7.
• Briccoli A, Rocca M, Salone M, Palmerini E, Balladelli A, Ferrari C, Di Fiore M, Bacci G. Local and systemic control of Ewing's bone sarcoma family tumors of the ribs. J Surg Oncol. 2009; 100(3): 222-6.
• Burchill SA. Ewing's sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol. 2003; 56(2): 96-102.
• Clinical trials.gov. Study in Localized and Disseminated Ewing sarcoma (EWING 2008). ClinicalTrials.gov Identifier: NCT00987636. Accessed December 2009 from: http://clinicaltrials.gov/ct2/show/NCT00987636
• Clinical trials.gov. Study Of CP-751,871 In Patients With Ewing's sarcoma Family Of Tumors. ClinicalTrials.gov Identifier: NCT00560235. Accessed December 2009 from: http://clinicaltrials.gov/ct2/show/NCT00560235?cond=%22Ewing%27s+sarcoma%22&rank=7
• Controlledtrials.com. EURO-EWING 99: European Ewing Tumour Working Initiative of National Groups, Combination chemotherapy with or without peripheral stem cell transplantation, radiation therapy, and/or surgery in treating patients with Ewing's sarcoma. Accessed December 2009 from: http://controlled-trials.com/ISRCTN61438620/61438620
• DiCaprio MR, Friedlaender GE. Malignant Bone Tumors: Limb Sparing Versus Amputation. J Am Acad Orthop Surg, 2003; 11(1): 25-37.
• Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003; 348(8): 694-701.
• Heare T, Hensley MA, Dell'Orfano S. Bone tumors: osteosarcoma and Ewing's sarcoma. Curr Opin Pediatr. 2009; 21(3): 365-72.
• Hughes DP. Novel agents in development for pediatric sarcomas. Curr Opin Oncol. 2009; 21(4): 332-7.
• Kauer M, Ban J, Kofler R, Walker B, Davis S, Meltzer P, Kovar H. A molecular function map of Ewing's sarcoma. PLoS One. 2009; 4(4): e5415.
• Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
• Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
• Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from: http://sarcomahelp.org/learning_center/ewings_sarcoma.html
• Ludwig JA. Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr Opin Oncol. 2008; 20(4): 412-8.
• Myatt SS, Burchill SA. The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38(MAPK) activity. Oncogene. 2008; 27(7): 985-96.
• Nicholson S, Mulvihill JJ, Byrne J. Late effects of therapy in adult survivors of osteosarcoma and Ewing's sarcoma. Med Pediatr oncol, 2006; 20(1): 6-12.
• Olmos D, Postel-Vinay S, Molife LR, Okuno SH, Schuetze SM, Paccagnella ML, Batzel GN, Yin D, Pritchard-Jones K, Judson I, Worden FP, Gualberto A, Scurr M, de Bono JS, Haluska P. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol. 2009 Dec 23. [Epub ahead of print].
• Ordóñez JL, Osuna D, Herrero D, de Alava E, Madoz-Gúrpide J. Advances in Ewing's sarcoma research: where are we now and what lies ahead? Cancer Res. 2009; 69(18):7140-50.
• Ordóñez JL, Martins AS, Osuna D, Madoz-Gúrpide J, de Alava E. Targeting sarcomas: therapeutic targets and their rational. Semin Diagn Pathol. Nov 2008; 25(4): 304-16.
• Paulidesa M, Dirksenb U, Stohra W, Jürgensb H, Dorra H-G, Bollingc T, Willichc N, Becka J-D, Langer T. Prospective follow-up of patients with ewing sarcoma within the late effects surveillance system. Pediatrics.121 Supplement January 2008, pp. S121.
• Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available at http://www.cure4kids.org/private/courses_documents/m_148/SIOP-2005-Education-Book.pdf
• Picarda G, Lamoureux F, Geffroy L, Delepine P, Montier T, Laud K, Tirode F, Delattre O, Heymann D, Rédini F. Preclinical evidence that use of TRAIL in Ewing's sarcoma and osteosarcoma therapy inhibits tumor growth, prevents osteolysis, and increases animal survival. Clin Cancer Res. 2010;16(8):2363-74. Epub 2010 Apr 6.
• Rowinsky EK, Youssoufian H, Tonra JR, Solomon P, Burtrum D, Ludwig DL. IMC-A12, a human IgG1 monoclonal antibody to the insulin-like growth factor I receptor. Clin Cancer Res. 2007;13(18 Pt 2): 5549s-5555s.
• Scurr M, Judson I. How to Treat the Ewing's Family of Sarcomas in Adult Patients. The Oncologist. 2006; 11(1): 65-72. Available at: http://theoncologist.alphamedpress.org/cgi/content/full/11/1/65
• Subbiah V, Anderson P, Lazar AJ, Burdett E, Raymond K, Ludwig JA. Ewing's sarcoma: standard and experimental treatment options. Curr Treat Options Oncol. 2009; 10(1-2):126-40.
• Toretsky JA, Gorlick R. IGF-1R targeted treatment of sarcoma. The Lancet Oncology. 2010; 11(2 ): 105 - 106.

Prognosis

• Burchill SA. Ewing's sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol. 2003; 56(2): 96-102.
• Cotterill SJ, Ahrens S, Paulussen M, Jürgens HF, Voûte PA, Gadner H, Craft AW.
• Prognostic Factors in Ewing's Tumor of Bone: Analysis of 975 Patients From the European Intergroup Cooperative Ewing's sarcoma Study Group. J Clin Oncol. 2000; 3108-3114.
• Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
• Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
• Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from: http://sarcomahelp.org/learning_center/ewings_sarcoma.html
• Leavey PJ, Collier AB. Ewing sarcoma: prognostic criteria, outcomes and future treatment. Expert Rev Anticancer Ther. 2008; 8(4): 617-24.
• Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available at http://www.cure4kids.org/private/courses_documents/m_148/SIOP-2005-Education-Book.pdf
• Rodríguez-Galindo C, Liu T, Krasin MJ, Wu J, Billups CA, Daw NC, Spunt SL, Rao BN, Santana VM, Navid F. Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies. Cancer. 2007; 110(2): 375-84. Free full text available from: http://www3.interscience.wiley.com/cgi-bin/fulltext/114278876/HTMLSTART Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from: http://emedicine.medscape.com/article/389464-overview